Chronic pain represents an immense clinical problem, with over 100 million Americans afflicted and an annual price tag exceeding half a trillion dollars according to a recent report from the Institute of Medicine. Although the past decade has seen a tremendous increase in our understanding of the neurobiology of pain and it pain sensitization, little progress has been made in improving therapy. We take the position that this gap in translation is due in part to the lack of studies demonstrating that the biological actions of agens used in preclinical animal studies are targeting the same systems and having similar physiological effects in humans prior to initiating clinical trials. With support from this grant, ver the past eleven years my lab has identified the activation of metabotropic glutamate receptor subtype 2/3 (mGlu2/3) in primary sensory neurons as an attractive target for the development of novel analgesic drugs. Pharmacologic activation of mGlu2/3 promotes analgesia, and in fact mGlu2/3 activation appears to be an endogenous mechanism for the resolution of hyperalgesia. We have further demonstrated that enhancing this pathway by promoting epigenetic upregulation of mGlu2 expression with L-acetyl Carnitine (LAC) therapy or using histone deacetylase (HDAC) inhibitors like SAHA (Vorinostat) can promote resolution of hyperalgesia after never injury. These results are consistent with the hypothesis that enhancing mGlu2/3 signaling pharmacologically or via epigenetic regulation can enhance endogenous mechanisms of resolution of chronic pain. This is particularly exciting due to the fact that mGlu2/3 agonists and mGlu2 positive allosteric modulators are in advanced clinical development, and HDAC inhibitors and LAC can be used in patients currently. In this application, we propose a series of studies that aim to 1) clarify the mechanisms of analgesia of these agents in animal models; 2) ask whether tolerance occurs in response to analgesic doses of mGlu2 positive allosteric modulators, and whether epigenetic upregulation of mGlu2 expression can prevent tolerance to mGlu2/3 agonists and PAMs, and 3) provide critical data linking animal studies to human physiology by examining the similarities in mGlu2/3 expression in human vs. mouse dorsal root ganglia, and whether the actions of mGlu2/3 on nociceptor physiology observed in mice is similar in human DRG neurons. In this way, we will provide data critical to effective translation o the preclinical data into new therapies for the treatment of chronic pain.